The invention relates to a process for the preparation of 4-alkoxyalkyl .beta.-carboline derivatives.
.beta.-Carbolines substituted in the 4-position by an alkoxyalkyl group exhibit a very good binding affinity to the benzodiazepine receptors, as has been disclosed in earlier applications, for example in EP-A No. 54,507; 161,575; 234,173; 130,140.
In accordance with the previously known method, the alkoxyalkyl group is already introduced at a quite early reaction step so that, for the production of alkoxyalkylated compounds, the entire .beta.-carboline synthesis must be run through. This synthesis is also made difficult by the fact that the aldehydes utilized must themselves be prepared in syntheses that are difficult to handle. Merely the methoxyacetaldehyde can be obtained commercially.
Therefore, the problem to be resolved resides in developing a widely applicable process for the preparation of 4-alkoxyalkyl .beta.-carbolines permitting the introduction of the alkoxyalkyl residue into diverse .beta.-carbolines in a simple way with high yields and in the presence of nontoxic compounds.
Etherification of the corresponding haloalkyl compound with alcoholates, which is an obvious procedure, leads primarily to undesired condensation products and has been accomplished only with the iodoalkyl compound, less readily accessible, and then also merely with ethanol in a poor yield.
However, when adding to the alcoholic solution of the .beta.-carboline silver tetrafluoroborate as the catalyst, the etherification is accomplished with a very good yield and purity of the product in a simple way with broad range of variation and without expensive separation operations or addition of toxic reaction additives.
The O-alkylation in the presence of silver salts has been reported on, for example, in the Merck Schuchardt O15 Info 84-4 reference. It can be seen from the latter that rearrangements take place frequently when using silver tetrafluoroborate.
It was therefore surprising that, under the claimed reaction conditions, etherification with aliphatic alcohols is achieved in one reaction step in good yields of 4-haloalkyl .beta.-carboline derivatives, wherein also sterically hindered alcohols, such as tert-butanol, and readily rearranging alcohols, such as cyclobutanol and cyclopropylmethanol can also be reacted.